Abstract Purpose Tumor hypoxia is a known cause of resistance to radiotherapy. The aim of this study was to investigate the prognostic value of hypoxia measured by18 F-fluoroazomycin arabinoside (18 ...F-FAZA) PET or the Eppendorf oxygen electrode in a pre-clinical tumor model. Material/methods Pretreatment18 F-FAZA PET scans and blood sampling was conducted in 92 Female CDF1 mice with subcutaneous C3H mammary carcinomas grown in the right foot. Similarly, oxygenation status of 80 equivalent tumors was assessed using an invasive oxygen sensitive electrode. Tumors were then irradiated with a single dose of 55 Gy and local tumor control up to 90 days after the treatment was determined. Results A significant difference in local tumor control between “more hypoxic” or “less hypoxic” groups separated either by a median18 F-FAZA PET determined tumor-to-blood ratio ( P = 0.007; hazard ratio, HR = 0.21 95% CI: 0.06–0.74), or the fraction of oxygen partial pressure (pO2 ) values ⩽2.5 mmHg ( P = 0.018; HR = 0.31 95% CI: 0.11–0.87), was found. Both assays showed that the more hypoxic tumors had significantly lower tumor control. Conclusion18 F-FAZA PET analysis showed that pre treatment tumor hypoxia was prognostic of radiation response. Similar results were obtained when oxygenation status was assessed by the Eppendorf pO2 Histograph. The results of this study support the role of18 F-FAZA as a non-invasive prognostic marker for tumor hypoxia.
Imaging hypoxia to improve radiotherapy outcome Horsman, Michael R; Mortensen, Lise Saksø; Petersen, Jørgen B ...
Nature reviews. Clinical oncology,
12/2012, Letnik:
9, Številka:
12
Journal Article
Recenzirano
Reduced oxygen levels (hypoxia) is one of the most important factors influencing clinical outcome after radiotherapy. This is primarily because hypoxic cells are resistant to radiation treatment; ...hence, the greater the number of clonogenic cancer stem cells that exist under hypoxia, the lower the local tumour control. Reduced local control will influence overall survival, as may the hypoxic conditions by increasing malignant progression; however, to fight hypoxia, we should first be able to see it. We need noninvasive approaches that can accurately and reliably image hypoxia in tumours, especially using techniques that are routinely available in the clinic, such as PET, MRI and CT. All these imaging methods are already under clinical evaluation in this context. Such data should allow us to identify those patients on an individual basis who have hypoxic tumours and, thus, at the very least should receive some form of hypoxic modifier in conjunction with radiotherapy. Alternatively, the radiation dose could be either increased to the whole tumour or, if the imaging is accurate enough, only to the hypoxic subvolumes. The aim of this Review is to critically assess the potential use of imaging to help improve clinical outcome to radiotherapy.
•18F-FAZA imaging was used in a prospective trial of 38 HNSCC patients completing radiotherapy.•Within 5 years of follow-up, nine locoregional treatment failures were observed.•A high tumor-muscle ...ratio of tracer uptake (TMR ≥1.6) was associated with a higher risk of locoregional failure.•This association remained significant, when accounting for HPV/p16-positivity.•FAZA PET likely identifies cases, where treatment intensification is indicated.
Hypoxic tumor volumes can be visualized with 18F-FAZA PET/CT. In head and neck squamous cell carcinoma (HNSCC), hypoxia is important for the clinical outcome after primary radiotherapy (RT). The outcome is furthermore heavily influenced by the HPV/p16-positivity of oropharyngeal tumors (OPCp16+ tumors). The study purposes were (1) to report on locoregional failures within five years after primary RT in a prospective cohort stratified by both HPV/p16-status and PET hypoxia and (2) to characterize the failure site and the spatial association to PET hypoxia.
From 2009 to 2011, 38 patients with non-metastatic SCC of the larynx, oro-, hypo- and nasopharynx completing primary RT were included in the prospective DAHANCA 24 trial (NCT01017224). Fifteen patients had OPCp16+ tumors. All were imaged with a static FAZA PET/CT prior to treatment. The hypoxia threshold was determined by a tumor-to-muscle ratio (TMR) of 1.6. Recurrences were documented histologically. Imaging of the recurrence was deformable fused with the pre-treatment FAZA PET/CT. The spatial information of recurrence- and hypoxic volumes were compared visually.
Sixteen patients had more hypoxic tumors (high tracer uptake, TMR ≥1.6) before treatment (42%). With a median follow-up of 7.8 years, nine locoregional recurrences were observed, of which seven were in patients with high-uptake tumors (44% and 9%, respectively, HR 5.8 1.2–28.2). The risk of locoregional recurrence was highest among patients with more hypoxic, non-OPCp16+ tumors (57% 21–94%), with a risk difference of 45% 4–86%, when comparing to less hypoxic, non-OPCp16+ tumors. Eight patients had sufficient imaging of the recurrence for co-registration with the FAZA PET/CT. Six had hypoxic primary tumors, and in two, the recurrence was overlapping the baseline hypoxic subvolume.
HNSCC demonstrating a TMR ≥1.6 at baseline is significantly associated with treatment failure after primary RT. In addition to HPV/p16-status, FAZA PET/CT has potential for the selection of tumors requiring treatment intensification.
Abstract Purpose Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate18 ...F-fluoroazomycin arabinoside (FAZA) positron emission tomography (PET)/computed tomography (CT) hypoxia imaging as a prognostic factor in HNSCC patients receiving radiotherapy. Material and methods Forty patients with HNSCC treated with radiotherapy (66–76 Gy) were included. Static FAZA PET/CT imaging 2 h post injection was conducted prior to irradiation. The hypoxic volume (HV) was delineated using a tumor-to-muscle value ⩾1.4. In 13 patients, a repetitive FAZA PET/CT scan was conducted during the radiotherapy treatment. Results A hypoxic volume could be identified in 25 (63%) of the 40 tumors. FAZA PET HV varied considerably with a range from 0.0 to 30.9 (median: 0.3) cm3 . The Tmax /Mmed ranged from 1.1 to 2.9 (median: 1.5). The distribution of hypoxia among the Human Papillomavirus (HPV) positive (12/16) and negative (13/24) tumors was not significant different. In the FAZA PET/CT scans performed during radiotherapy, hypoxia could be detected in six of the 13 patients. For these six patients the location of HV remained stable in location during radiotherapy treatment, though the size of the HV decreased. In 30 patients a positive correlation was detected between maximum FAZA uptake in the primary tumor and the lymph node. During a median follow up of 19 months a significant difference in disease free survival rate with 93% for patients with non hypoxic tumors and 60% for patients with hypoxic tumors could be detected. Conclusion This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC.
Blood-based protein biomarkers can be a useful tool as pre-treatment prognostic markers, as they can reflect both variations in the tumor microenvironment and the host immune response. We ...investigated the influence of a panel of plasma proteins for the development of any failure defined as recurrent disease in the T-, N-, or M-site in HNSCC.
We used a multiplex bead-based approach to analyze 19 proteins in 86 HNSCC patients and 15 healthy controls. We evaluated the associations between the biomarkers, loco-regional failure, failure in the T-, N-, or M-site, overall survival (OS), p16 status, and hypoxia.
In 41 p16 positive oropharynx cancer patients we identified a profile of biomarkers consisting of upregulation of IL-2, IL-4, IL-6, IL-8, eotaxin, GRO-a, and VEGF and downregulation of VEGFR-1 and VEGFR-2 with a significantly reduced risk of failure (p<0.01). None of the individual proteins were associated with outcome.
The identified plasma profile potentially reflects an activated immune response in a subgroup of the p16 positive patients.
Abstract
LET-painting was suggested as a method to overcome tumour hypoxia. In vitro experiments have demonstrated a well-established relationship between the oxygen enhancement ratio (OER) and ...linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation also increases the risk for side effects in normal tissue. LET-painting attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues. Methods. Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the tumour. The target dose is optimised to achieve a tumour control probability (TCP) of 95% when assuming a fully normoxic tissue. Using the same primary particle energy fluence needed for this plan, TCP is recalculated for three cases assuming hypoxia: first, redistributing LET to match the hypoxic structure (LET-painting). Second, plans are recalculated for varying hypoxic tumour volume in order to investigate the threshold volume where TCP can be established. Finally, a slight dose boost (5-20%) is additionally allowed in the hypoxic subvolume to assess its impact on TCP. Results. LET-painting with carbon-12 ions can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm3. Using oxygen-16 ions, tumour control can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm3. Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting. Conclusion. Our findings clearly indicate that a substantial increase in tumour control can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.
In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15-gene hypoxia ...classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here.
Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts DAHANCA 18 (n = 96), 24 (n = 40), and IAEA Hypo (n = 55) was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenograft tumors (FaDu
, UTSCC33), where gene expression in complementary sections was compared after fixation and embedding locally and at international institutions, respectively. Intra-tumor heterogeneity was addressed by classifying biopsy samples from HNSCC tumors, where 2-4 biopsies from each tumor was accessible.
Procedures were successfully established for individual classification of HNSCC patients in retrospective and prospective cohorts. Measurements of gene expression levels were reproducible between different international institutions.
Technical validation of the 15-gene hypoxia classifier demonstrated that it is suitable for implementation in prospective clinical trials.
Objective: To assess the usability of archived plasma and serum by multiplex (Luminex) analysis of circulating proteins (analytes) by evaluating the day to day variation, the effect of several ...freeze-thaw cycles, and the influence of the media and choice of anticoagulant.
Methods: Nineteen analytes in plasma and serum from 86 head and neck cancer patients and 33 controls were evaluated: EGFR, leptin, OPN, VEGFR-1, VEGFR-2, IL-2, IL-13, PDGF-bb, TNF, PAI-1, SDF-1a, IL-4, IL-6, IL-8, eotaxin, G-CSF, VEGF, GRO-a, and HGF.
Results: The correlation between measurements of the same samples analyzed on different dates was reasonable. However, samples run on different dates could exhibit different absolute values. The 75th percentile of the fold differences for samples run on different dates was 2.2. No significant difference was found between one and four freeze-thaw cycles (except for HGF), and the correlation was high. We found significant differences in mean concentrations of the majority of analytes in different media and with different anticoagulants. Only the following analytes did not show difference in mean concentrations: EDTA plasma vs. serum: leptin and VEGFR-2, LH plasma vs. serum: IL-2, IL-13, and VEGF, LH plasma levels vs. EDTA plasma: IL-2 and IL-4.
Conclusion: Stored serum, LH plasma, and EDTA plasma from clinical trials can be used for analysis of circulating cytokines and proteins. Variations in measurements occur, but are within reasonable ranges. The optimal type of media depends on the analytes, as different analytes have low number of measurements below the lower limit of quantification and higher dynamic ranges in different media.
•The two most commonly used hypoxia PET tracers FMISO and FAZA can be analyzed jointly.•Hypoxia PET derived parameters delivered strong and independent prognostic value.•Hypoxia specific treatment ...did not improve outcome in exploratory post hoc analyses.
Tumor hypoxia plays an important role in head and neck squamous cell carcinomas (HNSCC). Various positron emission tomography (PET) tracers promise non-invasive assessment of tumor hypoxia. So far, the applicability of hypoxia PET is hampered by monocentric imaging trials with few patients.
Multicenter individual patient data based meta-analysis of the original PET data from four prospective imaging trials was performed. All patients had localized disease and were treated with curatively intended radio(-chemo)therapy. Hypoxia PET imaging was performed with 18F-Fluoromisonidazole (FMISO, 102 patients) or 18F-Fluoroazomycin-arabinoside (FAZA, 51 patients). Impact of hypoxia PET parameters on loco-regional control (LRC) and overall survival (OS) was analyzed by uni- and multivariable Cox regression.
Baseline characteristics between participating centers differed significantly, especially regarding T stage (p < 0.001), tumor volume (p < 0.001) and p16 status (p = 0.009). The commonly used hypoxia parameters, maximal tumor-to-muscle ratio (TMRmax) and hypoxic volume with 1.6 threshold (HV1.6), showed a strong association with LRC (p = 0.001) and OS (p < 0.001). These findings were irrespective of the radiotracer and the same cut-off values could be applied for FMISO and FAZA (TMRmax > 2.0 or HV1.6 > 1.5 ml). The effect size of TMRmax was similar for subgroups of patients defined by radiotracer, p16 status and FDG-PET parameters for LRC and OS, respectively.
PET measured hypoxia is robust and has a strong impact on LRC and OS in HNSCC. The most commonly investigated tracers FMISO and FAZA can probably be used equivalently in multicenter trials. Optimal strategies to improve the dismal outcome of hypoxic tumors remain elusive.
Abstract
Introduction. Polarographic oxygen-sensitive electrodes have demonstrated prognostic significance of hypoxia. However, its routine application is limited. 18F-FMISO PET scans are a ...noninvasive approach, able to measure spatial and temporal changes in hypoxia. The aim of this study was to examine the association between measures of hypoxia defined by functional imaging and Eppendorf pO2 electrodes. Materials and methods. A total of 18 patients were included, nine squamous cell carcinoma of the head and neck and nine soft tissue tumors. The tumor volume was defined by CT, MRI, 18FDG-PET or by clinical examination. The oxygenation status of the tumors was assessed using 18F-FMISO PET imaging followed by Eppendorf pO2 electrode measurements. Data were compared in a 'virtual voxel', resulting in individual histograms from each tumor. Results. The percentages of pO2 ≤ 5 mmHg ranged from 9 to 94% (median 43%) for all 18 tumors. For 18F-FMISO PET the T/M ratio ranged from 0.70 to 2.38 (median 1.13). Analyzing the virtual voxel histograms tumors could be categorized in three groups: Well oxygenated tumors with no hypoxia and concordance between the 18F-FMISO data and the Eppendorf measurements, hypoxic tumors likewise with concordance between the two assays and inconclusive tumors with no concordance between the assays. Conclusion. This study analyzed the relationship between 18F-FMISO PET and Eppendorf pO2 electrode measurements by use of a virtual voxel model. There was a spectrum of hypoxia among tumors that can be detected by both assays. However no correlation was observed, and in general tumors were more hypoxic based on Eppendorf pO2 measurements as compared to 18F-FMISO PET.
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